Acute renal failure occurs in 55–70% of patients with STEC-HUS, although up to 70–85% recover renal function. Patients with aHUS generally have poor outcomes, with up to 50% progressing to ESRD or irreversible brain damage; as many as 25% die during the acute phase. However, with aggressive treatment, more than 90% of patients survive the acute phase of HUS, and only about 9% may develop ESRD. Roughly one-third of persons with HUS have abnormal kidney function many years later, and a few require long-term dialysis. Another 8% of persons with HUS have other lifelong complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of having part of their colon removed. The overall mortality rate from HUS is 5–15%. Children and the elderly have a worse prognosis.

aHUS can be inherited or acquired, and does not appear to vary by race, gender, or geographic area. As expected with an ultra-rare disease, data on the prevalence of aHUS are extremely limited. A pediatric prevalence of 3.3 cases per million population is documented in one publication of a European hemolytic uremic syndrome (HUS) registry involving 167 pediatric patients.

Atypical HUS (aHUS) represents 5–10% of HUS cases and is largely due to one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of complement. This results in platelet activation endothelial cell damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis (breakdown of red blood cells), damage to multiple organs, and ultimately death. Early signs of systemic complement-mediated TMA include thrombocytopenia (platelet count below 150,000 or a decrease from baseline of at least 25%) and evidence of microangiopathic hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased hemoglobin (the oxygen-containing component of blood), and/or the presence of schistocytes. Despite the use of supportive care, an estimated 33–40% of patients will die or have end-stage renal disease (ESRD) with the first clinical manifestation of aHUS, and 65% of patients will die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI) therapy. Patients who survive the presenting signs and symptoms of aHUS endure a chronic thrombotic and inflammatory state, which puts them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death.

Historically, treatment options for aHUS were limited to plasma exchange or plasma infusion (PE/PI) therapy, which carries significant safety risks and has not been proven effective in any controlled clinical trials. Patients with aHUS and ESRD have also had to undergo lifelong dialysis, which has a 5-year survival rate of 34–38%. In recent years the monoclonal antibody eculizumab (INN and USAN, trade name Soliris), a first-in-class terminal complement inhibitor, has been shown in clinical studies to block terminal complement activity in children and adults with aHUS, and to eliminate the need for PE/PI and new dialysis. In these studies eculizumab was associated with reduced TMA activity, as shown by improvement in platelet counts and kidney function, as well as hematologic normalization, complete TMA response, and TMA event-free status in a majority of patients.

Atypical hemolytic uremic syndrome (aHUS) has also been referred to as diarrhea-negative hemolytic-uremic syndrome (D HUS).

In 2003, the incidence of Rh(D) sensitization in the United States was 6.8 per 1000 live births; 0.27% of women with an Rh incompatible fetus experience alloimmunization.

Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. It can be divided in the following manner:

- Drug-induced autoimmune hemolytic anemia

- Drug-induced nonautoimmune hemolytic anemia

A total of four mechanisms are usually described, but there is some evidence that these mechanisms may overlap.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

Secondary TTP is diagnosed when the patient's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:

- Cancer

- Bone marrow transplantation

- Pregnancy

- Medication use:

- Antiviral drugs (acyclovir)

- Certain chemotherapy medications such as gemcitabine and mitomycin C

- Quinine

- Oxymorphone

- Quetiapine

- Bevacizumab

- Sunitinib

- Platelet aggregation inhibitors (ticlopidine, clopidogrel, and prasugrel)

- Immunosuppressants (ciclosporin, mitomycin, tacrolimus/FK506, interferon-α)

- Hormone altering drugs (estrogens, contraceptives, hormone replacement therapy)

- HIV-1 infection

The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage, although the formation of thrombi resulting in vessel occlusion may not be essential in the pathogenesis of secondary TTP. These factors may also be considered a form of secondary aHUS; patients presenting with these features are, therefore, potential candidates for anticomplement therapy.

The mortality rate is around 95% for untreated cases, but the prognosis is reasonably favorable (80–90% survival) for patients with idiopathic TTP diagnosed and treated early with plasmapheresis.

Complications of HDN could include kernicterus, hepatosplenomegaly, inspissated (thickened or dried) bile syndrome and/or greenish staining of the teeth, hemolytic anemia and damage to the liver due to excess bilirubin. Similar conditions include acquired hemolytic anemia, congenital toxoplasma and syphilis infection, congenital obstruction of the bile duct and cytomegalovirus infection.

- High at birth or rapidly rising bilirubin

- Prolonged hyperbilirubinemia

- Bilirubin Induced Neuorlogical Dysfunction

- Cerebral Palsy

- Kernicterus

- Neutropenia

- Thrombocytopenia

- Hemolytic Anemia - MUST NOT be treated with iron

- Late onset anemia - Must NOT be treated with iron. Can persist up to 12 weeks after birth.

The incidence of acute TTP in adults is around 1.7–4.5 per million and year. These cases are nearly all due to the autoimmune form of TTP, where autoantibodies inhibit ADAMTS13 activity. The prevalence of USS has not yet been determined but is assumed to constitute less than 5% of all acute TTP cases. The syndrome's inheritance is autosomal recessive, and is more often caused by compound heterozygous than homozygous mutations. The age of onset is variable and can be from neonatal age up to the 5th–6th decade. The risk of relapses differs between affected individuals. Minimization of the burden of disease can be reached by early diagnosis and initiation of prophylaxis if required.

Once a woman has antibodies, she is at high risk for a transfusion reaction. For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.

"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures"

Summary of transfusion reactions in the US

Once a woman has antibodies, she is at high risk for a transfusion reaction. For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.

"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."

Summary of transfusion reactions in the US.

Suggestions have been made that women of child bearing age or young girls should not be given a transfusion with Kell positive blood. Donated blood is not currently screened (in the U.S.A.) for the Kell blood group antigens as it is not considered cost effective at this time.

It has been hypothesized that IgG anti-Kell antibody injections would prevent sensitization to RBC surface Kell antigens in a similar way that IgG anti-D antibodies (Rho(D) Immune Globulin) are used to prevent Rh disease, but the methods for IgG anti-Kell antibodies have not been developed at the present time.

The specific cause is dependent of the type of TMA that is presented, but the two main pathways that lead to TMA are external triggers of vascular injury, such as viruses, bacterial Shiga toxins or endotoxins, antibodies, and drugs; and congenital predisposing conditions, including decreased levels of tissue factors necessary for the coagulation cascade. Either of these pathways will result in decreased endothelial thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, enhanced vascular shear stress, and abnormal vWF fragmentation. The central and primary event in this progression is injury to the endothelial cells, which reduces the production of prostaglandin and prostacyclin, ultimately resulting in the loss of physiological thromboresistance, or high thrombus formation rate in blood vessels. Leukocyte adhesion to the damaged endothelial wall and abnormal von Willebrand factor (or vWF) release can also contribute to the increase in thrombus formation. More recently, researchers have attributed both TTP and HUS to targeted agents, such as targeted cancer therapies, immunotoxins, and anti-VEGF therapy.

Bacterial toxins are the primary cause of one category of thrombotic microangiopathy known as HUS or hemolytic uremic syndrome. HUS can be divided into two main categories: Shiga-toxin-associated HUS (STx-HUS), which normally presents with diarrhea, and atypical HUS. The Shiga-toxin inhibits the binding of eEF-1-dependent binding of aminoacyl tRNA to the 60S subunit of the ribosome, thus inhibiting protein synthesis. The cytotoxicity from the lack of protein damages glomerular endothelial cells by creating voids in the endothelial wall and detaching the basement membrane of the endothelial layer, activating the coagulation cascade. Atypical HUS may be caused by an infection or diarrheal illness or it may be genetically transmitted. This category of TMA encompasses all forms that do not have obvious etiologies. Mutations in three of the proteins in the complement cascade have been identified in patients with atypical HUS. Several chemotherapeutic drugs have also been shown to cause damage to the epithelial layer by reducing the ability for the cells to produce prostacyclin, ultimately resulting in chemotherapy-associated HUS, or C-HUS.

The second category of TMAs is TTP thrombotic thrombocytopenic purpura, which can be divided into 3 categories: congenital, idiopathic, and non-idiopathic. Congenital and idiopathic TTP are generally associated with deficiencies in ADAMTS13, a zinc metalloprotease responsible for cleaving Very Large vWF Multimers in order to prevent inappropriate platelet aggregation and thrombosis in the microvasculature. Natural genetic mutations resulting in the deficiency of ADAMTS13 have been found in homozygous and heterozygous pedigrees in Europe. Researchers have identified common pathways and links between TTP and HUS, while other sources express skepticism about their common pathophysiology.

The repression of the vascular endothelial growth factor (VEGF) can also cause glomerular TMA (damage to the glomerular microvasculature). It is likely that the absence of VEGF results in the collapse of fenestrations in the glomerular endothelium, thus causing microvascular injury and blockages associated with TMA.

Manifestations resembling thrombotic microangiopathy have been reported in clinical trials evaluating high doses of Valacyclovir (8000 mg/day) administered for prolonged periods (months to years) for prophylaxis of cytomegalovirus (CMV) infection and disease, particularly in persons with HIV infection. A number of factors may have contributed to the incidence of thrombotic microangiopathy in those trials including profound immunosuppression, underlying diseases (advanced HIV disease, graft-versus-host disease), and other classes of drug, particularly antifungal agents. There were no reports of thrombotic microangiopathy among the 3050 subjects in the four trials evaluating Valacyclovir for suppression of recurrent genital herpes. Although one of the trials was in HIV-infected subjects, the patients did not have advanced HIV disease. The implication is that the occurrence of thrombotic microangiopathy is restricted to severely immunosuppressed persons receiving higher Valacyclovir dosages than are required to control HSV infection.

In some cases, the direct coombs will be negative but severe, even fatal HDN can occur. An indirect coombs needs to be run in cases of anti-C, anti-c, and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.

The clinical presentation of TMA, although dependent on the type, typically includes: fever, microangiopathic hemolytic anemia (see schistocytes in a blood smear), renal failure, thrombocytopenia and neurological manifestations. Generally, renal complications are particularly predominant with Shiga-toxin-associated hemolytic uremic syndrome (STx-HUS) and atypical HUS, whereas neurologic complications are more likely with TTP. Individuals with milder forms of TTP may have recurrent symptomatic episodes, including seizures and vision loss. With more threatening cases of TMA, and also as the condition progresses without treatment, multi-organ failure or injury is also possible, as the hyaline thrombi can spread to and affect the brain, kidneys, heart, liver, and other major organs.

Several therapy developments for TTP emerged during recent years. Artificially produced ADAMTS13 has been used in mice and testing in humans has been announced. Another drug in development is targeting VWF and its binding sites, thereby reducing VWF-platelet interaction, especially on ULVWF during a TTP episode. Among several (multi-)national data bases a worldwide project has been launched to diagnose USS patients and collect information about them to gain new insights into this rare disease with the goal to optimize patient care.

Most Rh disease can be prevented by treating the mother during pregnancy or promptly (within 72 hours) after childbirth. The mother has an intramuscular injection of anti-Rh antibodies (Rho(D) immune globulin). This is done so that the fetal rhesus D positive erythrocytes are destroyed before the immune system of the mother can discover them and become sensitized. This is passive immunity and the effect of the immunity will wear off after about 4 to 6 weeks (or longer depending on injected dose) as the anti-Rh antibodies gradually decline to zero in the maternal blood.

It is part of modern antenatal care to give all rhesus D negative pregnant women an anti-RhD IgG immunoglobulin injection at about 28 weeks gestation (with or without a booster at 34 weeks gestation). This reduces the effect of the vast majority of sensitizing events which mostly occur after 28 weeks gestation. Giving Anti-D to all Rhesus negative pregnant women can mean giving it to mothers who do not need it (because her baby is Rhesus negative or their blood did not mix). Many countries routinely give Anti-D to Rhesus D negative women in pregnancy. In other countries, stocks of Anti-D can run short or even run out. Before Anti-D is made routine in these countries, stocks should be readily available so that it is available for women who need Anti-D in an emergency situation.

A recent review found research into giving Anti-D to all Rhesus D negative pregnant women is of low quality. However the research did suggest that the risk of the mother producing antibodies to attack Rhesus D positive fetal cells was lower in mothers who had the Anti-D in pregnancy. There were also fewer mothers with a positive kleihauer test (which shows if the mother’s and unborn baby’s blood has mixed).

Anti-RhD immunoglobulin is also given to non-sensitized rhesus negative women immediately (within 72 hours—the sooner the better) after potentially sensitizing events that occur earlier in pregnancy.

The discovery of cell-free DNA in the maternal plasma has allowed for the non-invasive determination of the fetal RHD genotype. In May 2017, the Society for Obstetrics and Gynecology of Canada is now recommending that the optimal management of the D-negative pregnant woman is based on the prediction of the fetal D-blood group by cell-free DNA in maternal plasma with targeted antenatal anti-D prophylaxis. This provides the optimal care for D-negative pregnant women and has been adopted as the standard approach in a growing number of countries around the world. It is no longer considered appropriate to treat all D-negative pregnant women with human plasma derivatives when there are no benefits to her or to the fetus in a substantial percentage of cases.

During any pregnancy a small amount of the baby's blood can enter the mother's circulation. If the mother is Rh negative and the baby is Rh positive, the mother produces antibodies (including IgG) against the rhesus D antigen on her baby's red blood cells. During this and subsequent pregnancies the IgG is able to pass through the placenta into the fetus and if the level of it is sufficient, it will cause destruction of rhesus D positive fetal red blood cells leading to the development of Rh disease. It may thus be regarded as insufficient immune tolerance in pregnancy. Generally rhesus disease becomes worse with each additional rhesus incompatible pregnancy.

The main and most frequent sensitizing event is child birth (about 86% of sensitized cases), but fetal blood may pass into the maternal circulation earlier during the pregnancy (about 14% of sensitized cases). Sensitizing events during pregnancy include c-section, miscarriage, therapeutic abortion, amniocentesis, ectopic pregnancy, abdominal trauma and external cephalic version. However, in many cases there was no apparent sensitizing event.

The incidence of Rh disease in a population depends on the proportion that are rhesus negative. Many non-Caucasian people have a very low proportion who are rhesus negative, so the incidence of Rh disease is very low in these populations. In Caucasian populations about 1 in 10 of all pregnancies are of a rhesus negative woman with a rhesus positive baby. It is very rare for the first rhesus positive baby of a rhesus negative woman to be affected by Rh disease. The first pregnancy with a rhesus positive baby is significant for a rhesus negative woman because she can be sensitized to the Rh positive antigen. In Caucasian populations about 13% of rhesus negative mothers are sensitized by their first pregnancy with a rhesus positive baby. Without modern prevention and treatment, about 5% of the second rhesus positive infants of rhesus negative women would result in stillbirths or extremely sick babies. Many babies who managed to survive would be severely ill. Even higher disease rates would occur in the third and subsequent rhesus positive infants of rhesus negative women. By using anti-RhD immunoglobulin (Rho(D) immune globulin) the incidence is massively reduced.

Rh disease sensitization is about 10 times more likely to occur if the fetus is ABO compatible with the mother than if the mother and fetus are ABO incompatible.

The best known of these strains is , but non-O157 strains cause an estimated 36,000 illnesses, 1,000 hospitalizations and 30 deaths in the United States yearly. Food safety specialists recognize "Big Six" strains; O26, O45, O103, O111, O121, and O145. A was caused by another STEC, . This strain has both enteroaggregative and enterohemorrhagic properties. Both the O145 and O104 strains can cause hemolytic-uremic syndrome; the former strain shown to account for 2% to 51% of known HUS cases; an estimated 56% of such cases are caused by O145 and 14% by other EHEC strains.

EHECs that induce bloody diarrhea lead to HUS in 10% of cases. The clinical manifestations of postdiarrheal HUS include acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. The verocytotoxin (shiga-like toxin) can directly damage renal and endothelial cells. Thrombocytopenia occurs as platelets are consumed by clotting. Hemolytic anemia results from intravascular fibrin deposition, increased fragility of red blood cells, and fragmentation.

Antibiotics are of questionable value and have not shown to be of clear clinical benefit. Antibiotics that interfere with DNA synthesis, such as fluoroquinolones, have been shown to induce the Stx-bearing bacteriophage and cause increased production of toxins. Attempts to block toxin production with antibacterials which target the ribosomal protein synthesis are conceptually more attractive. Plasma exchange offers a controversial but possibly helpful treatment. The use of antimotility agents (medications that suppress diarrhea by slowing bowel transit) in children under 10 years of age or in elderly patients should be avoided, as they increase the risk of HUS with EHEC infections.

The clinical presentation ranges from a mild and uncomplicated diarrhea to a hemorrhagic colitis with severe abdominal pain. Serotype O157:H7 may trigger an infectious dose with 100 bacterial cells or fewer; other strain such as 104:H4 has also caused an outbreak in Germany 2011. Infections are most common in warmer months and in children under five years of age and are usually acquired from uncooked beef and unpasteurized milk and juice. Initially a non-bloody diarrhea develops in patients after the bacterium attaches to the epithelium or the terminal ileum, cecum, and colon. The subsequent production of toxins mediates the bloody diarrhea. In children, a complication can be hemolytic uremic syndrome which then uses cytotoxins to attack the cells in the gut, so that bacteria can leak out into the blood and cause endothelial injury in locations such as the kidney by binding to globotriaosylceramide (Gb3).

The disease is regarded as extremely rare, with an incidence (new number of cases per year) of one case per million people. The patients are predominantly male (86% in a survey of American patients), although in some countries the rate of women receiving a diagnosis of Whipple's disease has increased in recent years. It occurs predominantly in those of Caucasian ethnicity, suggesting a genetic predisposition in that population.

"T. whipplei" appears to be an environmental organism that is commonly present in the gasterointestinal tract but remains asymptomatic. Several lines of evidence suggest that some defect—inherited or acquired—in immunity is required for it to become pathogenic. The possible immunological defect may be specific for "T. whipplei", since the disease is not associated with a substantially increased risk of other infections.

The disease is usually diagnosed in middle age (median 49 years). Studies from Germany have shown that age at diagnosis has been rising since the 1960s.

Shigatoxigenic "Escherichia coli (STEC) and verotoxigenic "E. coli (VTEC) are strains of the bacterium "Escherichia coli" that produce either Shiga toxin or Shiga-like toxin (verotoxin). Only a minority of the strains cause illness in humans. The ones that do are collectively known as enterohemorrhagic "E. coli" (EHEC) and are major causes of foodborne illness. When infecting humans, they often cause gastroenteritis, enterocolitis, and bloody diarrhea (hence the name "enterohemorrhagic") and sometimes cause the severe complication of hemolytic-uremic syndrome (HUS). The group and its subgroups are known by various names. They are distinguished from other pathotypes of intestinal pathogenic "E. coli" including enterotoxigenic "E. coli" (ETEC), enteropathogenic "E. coli" (EPEC), enteroinvasive "E. coli" (EIEC), enteroaggregative "E. coli" (EAEC), and diffusely adherent "E. coli" (DAEC).

Transmission may occur via consumption of contaminated water, or when people share personal objects. In places with wet and dry seasons, water quality typically worsens during the wet season, and this correlates with the time of outbreaks. In areas of the world with four seasons, infections are more common in the winter. Bottle-feeding of babies with improperly sanitized bottles is a significant cause on a global scale. Transmission rates are also related to poor hygiene, especially among children, in crowded households, and in those with pre-existing poor nutritional status. After developing tolerance, adults may carry certain organisms without exhibiting signs or symptoms, and thus act as natural reservoirs of contagion. While some agents (such as "Shigella") only occur in primates, others may occur in a wide variety of animals (such as "Giardia").

In the developed world "Campylobacter jejuni" is the primary cause of bacterial gastroenteritis, with half of these cases associated with exposure to poultry. In children, bacteria are the cause in about 15% of cases, with the most common types being "Escherichia coli", "Salmonella", "Shigella", and "Campylobacter" species. If food becomes contaminated with bacteria and remains at room temperature for a period of several hours, the bacteria multiply and increase the risk of infection in those who consume the food. Some foods commonly associated with illness include raw or undercooked meat, poultry, seafood, and eggs; raw sprouts; unpasteurized milk and soft cheeses; and fruit and vegetable juices. In the developing world, especially sub-Saharan Africa and Asia, cholera is a common cause of gastroenteritis. This infection is usually transmitted by contaminated water or food.

Toxigenic "Clostridium difficile" is an important cause of diarrhea that occurs more often in the elderly. Infants can carry these bacteria without developing symptoms. It is a common cause of diarrhea in those who are hospitalized and is frequently associated with antibiotic use. "Staphylococcus aureus" infectious diarrhea may also occur in those who have used antibiotics. Acute "traveler's diarrhea" is usually a type of bacterial gastroenteritis, while the persistent form is usually parasitic. Acid-suppressing medication appears to increase the risk of significant infection after exposure to a number of organisms, including "Clostridium difficile", "Salmonella", and "Campylobacter" species. The risk is greater in those taking proton pump inhibitors than with H2 antagonists.